Neural degeneration, or neurodegeneration, can be described as the progressive damage or death of neurones. Neurones are nerve cells in the brain whose primary function is to assist in the memory process. The damage or death of neurones leads to a gradual deterioration of the functions controlled by the affected part of the nervous system.
Neural degeneration often occurs as a result of oxidative stress. Oxidative stress occurs to the cells when the effects of pro-oxidants (such as free radicals, reactive oxygen and reactive nitrogen species) exceed the ability of anti-oxidants to neutralise them. When levels of free radicals or other pro-oxidants increase to such an extent, they can cause damage to cell membranes which in turn may result in cell death or damage to genetic material.
Neurodegenerative diseases are a group of disorders characterised by changes in normal neuronal functioning, leading, in most cases, to neuronal death. Most of these diseases are associated, especially in late stages, with severe neuronal loss.
With an ever increasing ageing population, progressively more individuals are affected by neurodegenerative diseases. According to the National Institute of Neurological Disorders and Stroke, there are more than 600 different types of neurological disorders.
Some of the most common types of neurological disorders include Alzheimer's disease, Parkinson's disease and multiple sclerosis.
The process of neural degeneration is often the result of glutamate excitotoxicity. Glutamate is a signalling chemical and under normal conditions the concentration of glutamate in a cell tends to be quite low. Glutamate is required at these low concentrations for crucial brain functions such as memory and learning. When glutamate concentrations increase, the process of neural degeneration begins.
When the brain is deprived of oxygen either due to a disease, such as a neurodegerative disease, a trauma, such as a closed head injury or due to an ischemic event such as a stroke, an abnormal build-up of glutamate occurs.
Neural degeneration takes place when glutamate attaches to receptor proteins on a cells surface. These N-methyl-D-aspartate (NMDA) receptors then open an excess of calcium channels causing the intracellular concentration of calcium to increase rapidly. Calcium ions activate phospholipase A (PLA), which in turn results in the release of arachidonic acid and superoxide radicals.
Neural degeneration continues from the destructive effects of oxidative radicals caused by the glutamate flood. The radicals cause disruption of essential reactions in the neurones and this leads to degeneration or death of the cell.
Neuroprotective agents that are able to block the NMDA receptor are useful as they are able to block the reaction caused by glutamate and therefore prevent neural degeneration.
Some neuroprotective agents, which block the NMDA receptor, have been studied in clinical trials in stroke patients. Dextrorphan was the first NMDA antagonist to be studied in human subjects, but is of limited use due to its side effects of hallucinations, agitation and hypotension.
Another drug, Selfotel, showed trends towards a higher mortality rate with patients treated with the drug rather than placebo, and as such the trials were halted. The drug Cerestat also had its trials terminated because of concerns with the benefit-to-risk ratio of the drug.
Clearly there is a significant requirement for an efficacious NMDA antagonist to prevent or treat neural degeneration.
Cannabinoids are a group of chemicals known to activate cannabinoid receptors in cells. These chemicals, which are found in cannabis plants, are also produced endogenously in humans and other animals, these are termed endocannabinoids. Synthetic cannabinoids are chemicals with similar structures to plant cannabinoids or endocannabinoids.
Plant cannabinoids can also be isolated such that they are “essentially pure” compounds. These isolated cannabinoids are essentially free of the other naturally occurring compounds, such as, other minor cannabinoids and molecules such as terpenes.
Essentially pure compounds have a degree of purity up to at least 95% by total weight. Some essentially pure cannabinoids (whether synthetic or isolated) have been suggested to be neuroprotective agents, either by direct antagonism of the NMDA receptor or by reducing the influx of calcium ions into the cell by another means such as binding with cannabinoid receptors.
It was discovered that glutamate toxicity could be prevented to some extent by isolated or synthetic tetrahydrocannabinol (THC) or cannabidiol (CBD), (Hampson et al. 1998). The cannabinoids were tested in vitro on neuronal cultures exposed to glutamate.
However further research from an in vivo study by the same group failed to find a difference between animals treated with isolated or synthetic CBD and the placebo treated animals (Rosenthal et al. 2000).
Surprisingly the applicants have found that the administration of cannabinoid-containing plant extracts, are more efficacious than essentially pure cannabinoids in the prevention of neural degeneration. In particular cannabinoid-containing plant extracts comprising as a predominant cannabinoid either tetrahydrocannabinol (THC) or cannabidiol (CBD) were particularly efficacious in the prevention of neural degeneration.
The term “cannabinoid-containing plant extract” is taken herein to refer to one or more plant extracts from the cannabis plant. A cannabinoid-containing plant extract contains in addition to one or more other cannabinoids, one or more non-cannabinoid components which are co-extracted with the cannabinoids from the plant material. Their respective ranges will vary according to the starting plant material and the extraction methodology used. Cannabinoid-containing plant extracts may be obtained by various means of extraction of cannabis plant material. Such means include but are not limited to: supercritical or subcritical extraction with CO2, extraction with hot gas and extraction with solvents.